Regulation of TNF-Related Apoptosis-Inducing Ligand on Primary CD4+T Cells by HIV-1: Role of Type I IFN-Producing Plasmacytoid Dendritic Cells

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 39; pp. 13974 - 13979
• Main Authors: Herbeuval, Jean-Philippe, Hardy, Andrew W., Boasso, Adriano, Anderson, Stephanie A., Dolan, Matthew J., Dy, Michel, Shearer, Gene M., Sela, Michael
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 27.09.2005; National Acad Sciences
• Subjects: AIDS; Apoptosis; Apoptosis Regulatory Proteins; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Biological Sciences; Blood; CD4 Antigens; CD4 Antigens - metabolism; CD4-Positive T-Lymphocytes; CD4-Positive T-Lymphocytes - immunology; Cultured cells; Cytometry; Dendritic Cells; Dendritic Cells - immunology; Dendritic Cells - metabolism; Dendritic Cells - virology; Hepatocyte Nuclear Factor 1-beta; Hepatocyte Nuclear Factor 1-beta - metabolism; HIV 1; HIV Envelope Protein gp120; HIV Envelope Protein gp120 - metabolism; HIV Infections; HIV Infections - immunology; HIV-1 - physiology; Humans; Infections; Interferon Type I; Interferon Type I - metabolism; Life Sciences; Ligands; Membrane Glycoproteins; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Signal Transduction; T lymphocytes; TNF-Related Apoptosis-Inducing Ligand; Trails; Tumor Necrosis Factor-alpha; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0505251102

TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, was suggested to contribute to HIV-1 pathogenesis by inducing CD4+T cell death characteristic of AIDS. We previously reported HIV-1-mediated, TRAIL-induced apoptosis in primary CD4+T cells in vitro and observed elevated levels of plasma TRAIL in HIV-1-infected patients. The present study elucidates the unresolved mechanism by which HIV-1 induces TRAIL expression on primary CD4+T cells. We demonstrate that the expression of TRAIL by primary CD4+T cells is regulated by IFN-α that is produced by HIV-1-stimulated plasmacytoid dendritic cells (pDCs). We also found that IFN-induced TRAIL is mediated by signal transducers and activators of transcription 1 and 2. We show that IFN-α production by HIV-1-activated pDCs is blocked by an early viral entry inhibitor of CD4-gp120 binding, but not by inhibitors of viral coreceptor binding. Our in vitro data are supported by the demonstration that anti-IFN-α and -β Abs inhibit apoptosis and TRAIL expression in CD4+T cells from HIV-1-infected patients. Our findings suggest a potential unique role of pDCs in the immuno-pathogenesis of HIV-1 infection by inducing the death molecule TRAIL.